Screening for 22q11 deletions in a schizophrenia population

Arinami, Tadao; Ohtsuki, Tsuyuka; Takase, Kaoru; Shimizu, Hideyuki; Yoshikawa, Takeo; Horigome, Hitoshi; Nakayama, Junko; Toru, Michio

doi:10.1016/s0920-9964(00)00192-4

Cited by 75 publications

(53 citation statements)

References 14 publications

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“…Therefore, failure to detect the PRODH deletion in our controls probably results from our limited sample size. It should also be noted that no interstitial deletion of chromosome 22q11 was found in our sample of patients, thus supporting recent reports 22,23 indicating that 22q11DS might be less common among adult psychotic patients than initially thought. 24 Our study demonstrates that several rare PRODH mutations but not common DNA polymorphisms are associated with hyperprolinemia.…”

Section: Discussionsupporting

confidence: 91%

Hyperprolinemia is a risk factor for schizoaffective disorder

et al. 2004

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DNA sequence variations within the 22q11 DiGeorge chromosomal region are likely to confer susceptibility to psychotic disorders. In a previous report, we identified several heterozygous alterations, including a complete deletion, of the proline dehydrogenase (PRODH) gene, which were associated with moderate hyperprolinemia in a subset of DSM III schizophrenic patients. Our objective was (i) to determine whether hyperprolinemia is associated with increased susceptibility for any of three psychiatric conditions (schizophrenia, schizoaffective disorder and bipolar disorder) and (ii) to establish a correlation between hyperprolinemia and PRODH genotypes. We have conducted a case-control study including 114 control subjects, 188 patients with schizophrenia, 63 with schizoaffective disorder and 69 with bipolar disorder. We report that, taking into account a confounding effect due to valproate treatment, hyperprolinemia is a risk factor for DSM IIIR schizoaffective disorder (P ¼ 0.02, Odds ratio ¼ 4.6, 95% confidence interval 1.3-16.3). We did not detect 22q11 interstitial deletions associated with the DiGeorge syndrome among the 320 patients of our sample and we found no association between common PRODH polymorphisms and any of the psychotic disorders. In contrast, we found that five rare PRODH alterations (including a complete PRODH deletion and four missense substitutions) were associated with hyperprolinemia. In several cases, two variations were present simultaneously, either in cis or trans in the same subject. A total of 11 from 30 hyperprolinemic subjects bore at least one genetic variation associated with hyperprolinemia. This study demonstrates that moderate hyperprolinemia is an An increased frequency of several psychotic disorders, such as children-onset schizophrenia, 1 schizophrenia, 2 and bipolar disorder, 3 has been observed in patients with the 22q11 deletion syndromes (22q11DS), 4 which include the DiGeorge syndrome (MIM 188400) and the velo-cardio-facial syndrome (MIM 192430). This has led to the hypothesis that sequence variations of one or several genes located within the 3 Mb region commonly deleted in most of the 22q11DS patients 5 might confer susceptibility for psychoses in the general population. In a previous study, we had identified in two schizophrenic relatives (diagnosed according to DSM III criteria) a 350 kb heterozygous deletion within the DiGeorge critical region (DGCR) removing entirely the proline dehydrogenase (PRODH) gene. This deletion was associated in patients with moderate hyperprolinemia. In addition, two heterozygous PRODH missense mutations (L441P and L289M) were detected in three of 63 schizophrenic patients but not in 68 controls, and these mutations were also associated with moderate hyperprolinemia. 6 Interestingly, we subsequently found the same PRODH deletion and the L441P substitution at the homozygous state in children suffering from a severe form of type I hyperprolinemia, a condition characterized by high plasma proline levels, seizures and mental retardation. 7 T...

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Section: Discussionsupporting

confidence: 91%

Hyperprolinemia is a risk factor for schizoaffective disorder

et al. 2004

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“…Description of studies A total of 18 [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] studies published between 1996 and 2003 were identified by the search strategy, met the inclusion criteria and contributed to the meta-analysis. This included four studies not included in the original meta-analysis.…”

Section: Resultsmentioning

confidence: 99%

Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case–control studies

et al. 2005

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There is strong evidence for a genetic contribution to schizophrenia, but the contribution of individual candidate genes remains uncertain. We attempted to replicate a recent metaanalysis that reported an association of the catechol O-methyltransferase (COMT) Val allele with schizophrenia, and suggested that this effect may be moderated by ancestry. We included reports published subsequent to the original meta-analysis, and included a formal test of the moderating effect of ancestry in order to test whether the association operates differently in populations of European ancestry compared to populations of Asian ancestry. A corrected Pvalue for the 5% significance threshold was employed where appropriate, using Bonferroni's method, and studies that demonstrated departure from Hardy-Weinberg equilibrium among controls were excluded. When all studies were included in a meta-regression, there was evidence for a significant association of COMT Val allele frequency with schizophrenia case status and a significant main effect of ancestry. The interaction of COMT Val allele frequency and ancestry was also significant. However, when only studies that reported allele frequencies that did not depart significantly from Hardy-Weinberg equilibrium among controls were included, these effects were no longer significant. The results of our meta-analysis do not support an association between the COMT Val allele and schizophrenia case status, and do not support recent claims that this association may be moderated by ancestry. Twin studies provide convincing evidence that susceptibility to schizophrenia is attributable largely to genetic factors, 1,2 but progress in identifying the specific genetic variants responsible has been slow. One approach is to look at genes involved in the metabolism of dopamine, on the hypothesis that schizophrenia is primarily caused by dysregulation of dopaminergic neurotransmission in corticostriatal circuits. 3 This is one reason why the gene coding for catechol O-methyltransferase (COMT) has attracted considerable attention as a potential candidate, as it inactivates catechols at postsynaptic sites in the human brain. COMT contains a functional polymorphism, a single-nucleotide polymorphism at position 108/158 that results in a change from valine (val) to methionine (met). The amino-acid change affects function of the enzyme: val-COMT has significantly lower enzyme activity than met-COMT. 4,5 An association between the functional Val 158/108 Met polymorphism of the COMT gene and schizophrenia has been investigated in a number of studies, but with equivocal results. The small effect sizes of putative candidate genes such as COMT may, however, result in the absence of significant association in individual studies with modest sample sizes. This may explain the conflicting findings that have been reported in repeated studies of this association.A recent meta-analysis 6 of case-control and familybased studies of the association between the COMT gene Val 158/108 Met polymorphism and schizophrenia concluded...

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“…Most case-control studies, as well as our study, have failed to find a significant association between COMT polymorphism and schizophrenia. 52,54,55,[59][60][61][82][83][84][85][86][87][88] A handful of case-control studies found that the high enzyme activity valine allele had a modest effect on conferring increased risk for schizophrenia. 58,63,89 Conversely, the methionine allele has also been reported to occur more frequently among schizophrenia patients than normal controls.…”

Section: Discussionmentioning

confidence: 99%

Catechol-O-methyl transferase Val158Met gene polymorphism in schizophrenia: working memory, frontal lobe MRI morphology and frontal cerebral blood flow

et al. 2005

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The catechol-O-methyl transferase (COMT) gene is considered a leading schizophrenia candidate gene. Although its role in increasing schizophrenia susceptibility has been conflicting, recent studies suggest the valine allele may contribute to poor cognitive function in schizophrenia. V 158 M COMT genotype was obtained on 159 schizophrenia patients and 84 healthy controls. The effects of COMT genotype on four measures of working memory/ executive functions (Wisconsin Card Sorting, digit span backward, Trail Making and N-back tests) and on MRI frontal brain volumes were examined. Genotype distributions were not significantly different between patients and controls. There were no significant genotype or genotype-by-group effects on any working memory/executive function measures. No genotype or genotype-by-diagnosis interaction effects were found with MRI frontal lobe volumes. Randomization analyses using [ 15 O]H 2 O positron emission tomography (PET) cerebral blood flow data found Val/Val patients had higher frontal lobe activation than Met/Met patients while performing the one-back task. Overall, these findings do not support a major role for COMT in increasing susceptibility for schizophrenia or in mediating frontal lobe function. Age-related changes and phenotypic heterogeneity of schizophrenia may influence the complex relationships between COMT genotype and cognition.

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Screening for 22q11 deletions in a schizophrenia population

Cited by 75 publications

References 14 publications

Hyperprolinemia is a risk factor for schizoaffective disorder

Hyperprolinemia is a risk factor for schizoaffective disorder

Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case–control studies

Catechol-O-methyl transferase Val158Met gene polymorphism in schizophrenia: working memory, frontal lobe MRI morphology and frontal cerebral blood flow

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